Versican accumulation drives Nos2 induction and aortic disease in Marfan syndrome via Akt activation.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.

Advancements in synthetic biology-based bacterial cancer therapy: A modular design approach.

Synthetic biology aims to program living bacteria cells with artificial genetic circuits for user-defined functions, transforming them into powerful tools with numerous applications in various fields, including oncology. Cancer treatments have serious side effects on patients due to the systemic action of the drugs involved. To address this, new systems that provide localized antitumoral action while minimizing damage to healthy tissues are required. Bacteria, often considered pathogenic agents, have been used as cancer treatments since the early 20th century. Advances in genetic engineering, synthetic biology, microbiology, and oncology have improved bacterial therapies, making them safer and more effective. Here we propose six modules for a successful synthetic biology-based bacterial cancer therapy, the modules include Payload, Release, Tumor-targeting, Biocontainment, Memory, and Genetic Circuit Stability Module. These will ensure antitumor activity, safety for the environment and patient, prevent bacterial colonization, maintain cell stability, and prevent loss or defunctionalization of the genetic circuit.

Characterization of Gene Circuit Parts Based on Multiobjective Optimization by Using Standard Calibrated Measurements.

Standardization and characterization of biological parts is necessary for the further development of bottom-up synthetic biology. Herein, an easy-to-use methodology that embodies both a calibration procedure and a multiobjective optimization approach is proposed to characterize biological parts. The calibration procedure generates values for specific fluorescence per cell expressed as standard units of molecules of equivalent fluorescein per particle. The use of absolute standard units enhances the characterization of model parameters for biological parts by bringing measurements and estimations results from different sources into a common domain, so they can be integrated and compared faithfully. The multiobjective optimization procedure exploits these concepts by estimating the values of the model parameters, which represent biological parts of interest, while considering a varied range of experimental and circuit contexts. Thus, multiobjective optimization provides a robust characterization of them. The proposed calibration and characterization methodology can be used as a guide for good practices in dry and wet laboratories; thus allowing not only portability between models, but is also useful for generating libraries of tested and well-characterized biological parts.